/* reaction_mechanisms.mdl */

/* ACh-AChR interactions */

DEFINE_REACTION AChR { /* reaction name is "AChR" */

/* Each state within a reaction mechanism implicitly defines a molecule that requires a name. Here the AChR states are given names of "R0", "AR1", "AR2", "A2R3", and "A2R4" to correspond with the reaction mechanism shown in book Fig. 4.1. Each state name is followed by a list of possible transition paths, one to each adjacent state. Each path is enclosed in square brackets. The general syntax for each path is:

state_name[>adjacent_state_name{rate_constant}]

if the transition is a simple conformational change, or

state_name[>adjacent_state_name{rate_constant: ?defined_molecule_name,polarity}]

if the transition includes an operation on another previously defined molecule. The "?" symbol is a placeholder for one of several types of molecular operation, e.g., a "+" or "-" is used in this reaction to indicate ligand binding or unbinding, respectively. For binding transitions, the second-order rate constant is given in liters/(mole second), while for all unimolecular transitions the first order rate constant is given in (1/second).

Since effector sites reside on mesh elements and the mesh elements have front and back faces, binding and unbinding operations have "polarity". The effector site itself is considered to have a positive and negative "pole" (this terminology has no necessary relation to charge), and when an effector site is placed on a mesh element, the site’s positive pole can be on either the element’s front or back face (e.g., see muscle_membrane.mdl). Then, in a reaction mechanism transition, polarity indicates whether the molecular event occurs on the effector site’s positive or negative pole (or both). Polarity is specified using several context-dependent keywords. In this AChR reaction for effector sites on the muscle membrane mesh, ACh binding and unbinding both occur on the positive pole, which faces the synaptic cleft diffusion space. */

R0[>AR1{1.35e8:+ACh,POSITIVE_POLE}][>AR2{1.35e8:+ACh,

POSITIVE_POLE}] /* An effector site in the R0 state has two independent ACh binding sites on its positive pole. Binding to one leads to the AR1 state; binding to the other leads to the AR2 state. In this example the two sites happen to be statistically identical because the specified rate constants are identical. */

AR1[>A2R3{1.35e8:+ACh,POSITIVE_POLE}][>R0{64286:-ACh,

POSITIVE_POLE}] /* The AR1 state has one remaining ACh binding site, or can unbind ACh from the occupied site on its positive pole. */

AR2[>A2R3{1.35e8:+ACh,POSITIVE_POLE}][>R0{64286:-ACh,

POSITIVE_POLE}] /* The AR2 state has one remaining ACh binding site, or can unbind ACh from the occupied site on its positive pole. */

A2R3[>A2R4{48750}][>AR1{64286:-ACh,POSITIVE_POLE}]

[>AR2{64286:-ACh,POSITIVE_POLE}] /* The A2R3 state can undergo a conformational change to the A2R4 state, or can unbind an ACh molecule from either of the two occupied sites on its positive pole. */

A2R4[>A2R3{1250}] /* The A2R4 state can only undergo a conformational change back to the A2R3 state. */

REFERENCE_STATE R0 {

ACh NUMBER_BOUND = 0

} /* To track the number of bound and unbound molecules correctly, a baseline is established by picking one (any) state (R0 in this case) and listing the number of molecules bound to it. */

}

/* ACh-AChE interactions */

DEFINE_REACTION AChE { /* State names correspond to the reaction mechanism shown in book Fig. 4.1. */

E[>AE{2.0e8:+ACh,BOTH_POLES}] /* Since AChE effector sites exist on the transparent basal lamina mesh within the synaptic cleft diffusion space (see basal_lamina.mdl and book Fig. 4.4A), ACh binding is allowed on both the positive and negative poles. */

AE[>AcE{112000:*Ch,EITHER_POLE}][>E{14000:-ACh,EITHER_POLE}] /* The transformation from AE to AcE produces (* operation) a diffusing Ch molecule from either the positive or negative pole, or the AE state can unbind ACh from either pole. */

AcE[>E{18667:#ACh}][>AAcE{5.0e6:+ACh,BOTH_POLES}] /* The transformation from AcE back to E irreversibly destroys (# operation) the ACh that had originally bound, or the AcE state can bind a second ACh molecule. */

AAcE[>AcE{21429:-ACh,EITHER_POLE}][>AE{1867:#ACh}] /* Unbinding or destruction can occur; destruction is slower than from the AcE state to simulate excess substrate inhibition. */

REFERENCE_STATE E {

ACh NUMBER_BOUND = 0

Ch NUMBER_BOUND = 0

} /* Both ACh and Ch participate in the reaction and must be listed. */

}

/* Re-uptake of Ch produced by ACh-AChE reaction */

DEFINE_REACTION ChR { /* State names must be unique within a reaction mechanism, but can be reused in different mechanisms (e.g., R0, AR1, and AR2 are used here and were also used previously in the AChR reaction). */

R0[>AR1{1.0e8:+Ch,POSITIVE_POLE}] /* Ch binds to the positive pole of reuptake effector sites on the nerve membrane mesh, i.e., from within the synaptic cleft (see nerve_membrane.mdl). */

AR1[>R0{1000:-Ch,POSITIVE_POLE}][>AR2{1.0e5}] /* Ch can unbind to reenter the synaptic cleft, or the AR1 state can flip to an alternate conformation. */

AR2[>R0{1000:-Ch,NEGATIVE_POLE}] /* From the AR2 state, Ch can unbind from the negative pole to diffuse within the nerve, i.e., the Ch molecule has been transported across the nerve membrane mesh. The effector site reenters the unbound R0 state. */

REFERENCE_STATE R0 {

Ch NUMBER_BOUND = 0

} /* Only Ch can participate and is listed. */

}